Chlymadia pneumoniae is a common respiratory pathogen of human diseases. Virtually everyone is infected at some point in life, and re-infection occurs commonly. Epidemiological and histological studies show that C. pneumoniae infection is one of the leading environmental factors of atherosclerosis. C. pneumoniae infects and replicates within macrophage, endothelial, and epithelial cells. Infection of C. pneumoniae induces adhesion molecule up-regulation, increases inflammatory factor release, and causes foam cell formation, although the receptor(s) that mediates bacterial cell attachment, the signaling events that promote bacterial cell entry remain poorly understood. This proposal seeks to identify receptors for C. pneumoniae infection and define the signaling pathways that promote bacterial cell entry and infection-induced gene expression. We will use functional cloning and proteomics to identify the proteins as putative C. pneumoniae attachment receptors. We will define signal transduction pathways controlling C. pneumoniae cell entry and the infection-induced up-regulation of adhesion and inflammation molecules. We will define bacterial outer membrane components for activating these signaling pathways. These studies will further our understanding of chlamydial cell entry mechanisms and may lead to the development of new therapeutics for chlamydial infections.